Newly developed preclinical models reveal broad-spectrum CDK inhibitors as potent drugs for CRPC exhibiting primary resistance to enzalutamide.

Androgen-deprivation therapy is a standard treatment for advanced prostate cancer. However, most patients eventually acquire resistance and progress to castration-resistant prostate cancer (CRPC). In this study, we established new CRPC cell lines, AILNCaP14 and AILNCaP15, from LNCaP cells under androgen-deprived conditions. Unlike most pre-existing CRPC cell lines, both cell lines expressed higher levels of androgen receptor (AR) and prostate-specific antigen (PSA) than parental LNCaP cells. Moreover, these cells exhibited primary resistance to enzalutamide. Since AR signaling plays a significant role in the development of CRPC, PSA promoter sequences fused with GFP were introduced into AILNCaP14 cells to conduct GFP fluorescence-based chemical screening. We identified flavopiridol, a broad-spectrum CDK inhibitor, as a candidate drug that could repress AR transactivation of CRPC cells, presumably through the inhibition of phosphorylation of AR on the serine 81 residue (pARSer81 ). Importantly, this broad-spectrum CDK inhibitor inhibited the proliferation of AILNCaP14 cells both in vitro and in vivo. Moreover, a newly developed liver metastatic model using AILNCaP15 cells revealed that the compound attenuated tumor growth of CRPC harboring highly metastatic properties. Finally, we developed a patient-derived xenograft (PDX) model of CRPC and DCaP CR from a patient presenting therapeutic resistance to enzalutamide, abiraterone, and docetaxel. Flavopiridol successfully suppressed the tumor growth of CRPC in this PDX model. Since ARSer81 was found to be phosphorylated in clinical CRPC samples, our data suggested that broad-spectrum CDK inhibitors might be a potent candidate drug for the treatment of CRPC, including those exhibiting primary resistance to enzalutamide.

Adaptive Dynamics Simulation of Interference Phenomenon for Physical and Biological Systems.

Biological systems have been shown to have quantum-like behaviors by applying the adaptive dynamics view on their interaction networks. In particular, in the process of lactose-glucose metabolism, cells generate probabilistic interference patterns similarly to photons in the two-slit experiment. Such quantum-like interference patterns can be found in biological data, on all scales, from proteins to cognitive, ecological, and social systems. The adaptive dynamics approach covers both biological and physical phenomena, including the ones which are typically associated with quantum physics. We guess that the adaptive dynamics can be used for the clarification of quantum foundations, and the present paper is the first step in this direction. We suggest the use of an algorithm for the numerical simulation of the behavior of a billiard ball-like particle passing through two slits by explicitly considering the influence of the two-slit environment (experimental context). Our simulation successfully mimics the interference pattern obtained experimentally in quantum physics. The interference of photons or electrons by two slits is known as a typical quantum mechanical effect. We do not claim that the adaptive dynamics can reproduce the whole body of quantum mechanics, but we hope that this numerical simulation example will stimulate further extensive studies in this direction-the representation of quantum physical phenomena in an adaptive dynamical framework.

Repeated ultrasound tests could be used to identify an isolated gastric duplication cyst before surgery.

A toddler girl was diagnosed with intra-abdominal simple cyst in the splenic flexure at the gestational period. Due to a severe fever that persisted for 6 days, she was admitted to the emergency room. The diagnosis of intraperitoneal cyst infection was made after contrast-enhanced CT revealed an enlarged cyst and a heterogeneous contrast effect on the cyst wall. A double-wall sign was observed on the cyst wall during continuous ultrasound follow-up, which led to the preoperative diagnosis of the cyst as a duplication cyst. The double-wall sign and cyst peristalsis were identified via successive ultrasound examinations to support the cyst diagnosis. Identifying a duplication cyst based solely on symptoms alone is difficult because the condition may present in different ways.

Efficacy and Tolerability of Second-line Pembrolizumab With Radiation Therapy in Advanced Urothelial Carcinoma.

BACKGROUND/AIM: Considering the limited data available on immune checkpoint inhibitors and radiation combination therapy in advanced urothelial carcinoma, this study evaluated the survival benefit and associated toxicity of adding radiation therapy to second-line pembrolizumab. PATIENTS AND METHODS: We retrospectively examined 24 consecutive patients with advanced bladder or upper urinary tract urothelial carcinoma and for whom second-line pembrolizumab was initiated between August 2018 and October 2021 in combination with radiation therapy (with curative intent in 12 patients, and palliative intent in 12 patients). Their survival outcomes and toxicities were compared with those of propensity-score-matched cohorts from a Japanese multicenter study with similar characteristics who received pembrolizumab monotherapy. RESULTS: The median follow-up periods after pembrolizumab initiation were 15 months for the curative cohort and 4 months for the palliative cohort. The median overall survival was 27.7 months for the curative cohort and 4.8 months for the palliative cohort. Compared with the matched pembrolizumab monotherapy cohort, overall survival was better among the curative cohort although not statistically significant (p=0.13), but similar between the palliative and matched pembrolizumab monotherapy cohorts (p=0.44). There was no difference in the incidence of grade ≥2 adverse events between the combination and monotherapy cohorts, irrespective of the intent of radiation therapy. CONCLUSION: The combination of radiation therapy and pembrolizumab can be performed with a clinically acceptable safety profile, and the addition of radiation therapy to immune checkpoint inhibitors may improve survival outcome after pembrolizumab treatment in cases where the intent of radiation therapy is curative.

Analysis of trifecta outcomes in a single center with robot-assisted partial nephrectomy for T1b renal tumors.

INTRODUCTION: This study was performed to investigate the preoperative factors associated with difficulty achieving trifecta in robot-assisted partial nephrectomy for clinical T1b renal cell carcinoma. METHODS: Among 187 patients who underwent robot-assisted partial nephrectomy at our hospital from March 2012 to February 2022, we retrospectively examined 30 patients with unilateral single clinical T1b renal cell carcinoma with at least 6 months of postoperative follow-up, excluding patients with hereditary disease. The following factors were examined in detail: patient-related factors, perioperative factors, surgical techniques, tumor factors, and R.E.N.A.L. nephrometry scores. We examined the preoperative factors associated with difficulty achieving trifecta. A positive surgical margin was pathologically defined as the presence of tumor cells at the margin of the resected specimen or visually defined as intraoperative tumor incision or pseudocapsular damage. RESULTS: Of the 30 patients in this study, 12 achieved trifecta and 18 did not. The reasons for not achieving trifecta were a warm ischemia time of >25 min (66.7%), positive surgical margin (23.3%), and Clavien-Dindo grade ≥3 complications (13.3%) (with overlapping factors). No patients had a pathologically positive surgical margin. Visually positive surgical margins were confirmed by the surgical records and surgical videos. Achieving trifecta was challenging in the multivariate analysis when the "L" component of the R.E.N.A.L. nephrometry score was ≥2 points. CONCLUSION: A preoperative "L" component of ≥2 points in the R.E.N.A.L. nephrometry score was associated with difficulty achieving trifecta.

Implant deformation and implant-abutment fracture resistance after standardized artificial aging: An in vitro study.

BACKGROUND AND PURPOSE: Zirconia abutments have been widely adopted in clinical implant practice. The unique mechanical properties of zirconia may significantly affect the long-term prognosis of implant treatments. The purpose of this study was to investigate the influence of abutment material on implant deformation and fracture resistance of internal conical connection implant-abutment complexes of two diameters after standardized artificial aging. MATERIALS AND METHODS: Thirty original abutments (one-piece titanium, one-piece zirconia, zirconia with alloy base) with two diameters (regular, narrow) were connected to internal conical connection implants and subjected to a standardized artificial aging process consisting of thermal cycling and mechanical cyclic loading. Microcomputed tomography (µCT) scans of implant bodies were performed before and after aging. 3-dimensional images of implant bodies were generated from the µCT scans and aligned for before and after aging to calculate the volumetric deformation amount. Finally, fracture resistance was measured using a mechanical static loading test for the surviving aged and 30 brand-new specimens. RESULTS: All specimens survived artificial aging. No significant difference in implant deformation was found in the regular groups (p = 0.095). In narrow groups, the one-piece zirconia group showed significantly less deformation (p < 0.0001). For fracture resistance, no significant decrease was observed after aging in any group (p > 0.05). One-piece zirconia abutments showed significantly lower strength than the other two materials for both diameters (p < 0.0001). CONCLUSIONS: In the regular diameter system, abutment material had no significant influence on the tested mechanical property degradation after simulated long-term oral use. The mechanical performance of narrow diameter one-piece zirconia abutments differed from the other two materials. For optimal performance, one-piece zirconia abutments should be adopted only in anterior regions.

Effect of continued perioperative antithrombotic therapy on bleeding outcomes following laparoscopic nephrectomy and nephroureterectomy.

INTRODUCTION: In this study, we aimed to assess the impact of perioperative continuation of antithrombotic therapy on bleeding and complications in patients undergoing laparoscopic radical nephrectomy (LRN) and nephroureterectomy (LNU). METHODS: This was a retrospective observational study. Patients who underwent LRN and LNU between January 2017 and July 2019 at our institution were recruited. All patients taking antithrombotic agents continued taking them during the perioperative phase (AA group). Surgical outcomes of patients in the AA group were compared with those of patients who were not taking antithrombotic agents (NA group). The primary outcome was the rate of bleeding complications. Secondary outcomes included intraoperative estimated blood loss, transfusion rate, and complications for up to 90 days. RESULTS: A total of 100 patients were included in the analysis, with 36 and 64 patients assigned to the AA and NA groups, respectively. Patients in the AA group were found to have more severe comorbidities than those in the NA group, with a Charlson Comorbidity Index ≥5, totaling 14 (39%) and 12 (19%), respectively (P = .03). According to surgical outcomes, none of the patients in the AA group required secondary procedures for bleeding complications. Moreover, there were no significant differences between the groups in intraoperative blood loss, hemoglobin deficit, rate of perioperative transfusion, readmission rate, or high-grade complications. DISCUSSION: These results indicate that perioperative use of antithrombotic agents does not increase the risk of bleeding and can be considered safe during LRN and LNU.

Abutment removal torque and implant conical surface morphological changes after standardized artificial aging: An in vitro study.

STATEMENT OF PROBLEM: Zirconia abutments have become popular as they provide favorable esthetic outcomes. However, studies investigating how abutment material affects abutment screw torque performance and implant conical surface morphological changes in internal conical connection systems are scarce. PURPOSE: The purpose of this in vitro study was to investigate the influence of abutment material on abutment removal torque and implant conical surface morphological changes in internal conical connection implant-abutment assemblies of 2 diameters after simulated long-term oral use. MATERIAL AND METHODS: Thirty abutments of 3 materials (1-piece titanium, 1-piece zirconia, zirconia with alloy base) and 2 diameters (regular, narrow) made by the original manufacturer were connected to internal conical connection implants and subjected to a standardized artificial aging process consisting of thermal cycling and mechanical cyclic loading with parameters corresponding to anterior and posterior mastication scenarios simulating long-term oral use. An abutment removal torque test was done before and after aging. Morphological changes in the implant conical contact surface were observed with a scanning electron microscope (SEM). Initial and after-aging torque loss values were calculated and analyzed separately with 1-way ANOVA and Tukey HSD post hoc tests (α=.05). RESULTS: All specimens survived artificial aging. For initial and after-aging torque loss, the 1-piece zirconia groups showed significantly greater values (P<.001) for both diameters. In the SEM observation, the 1-piece zirconia groups showed distinct widespread surface damage while the other groups exhibited only minor damages. CONCLUSIONS: Regardless of diameter, 1-piece zirconia abutments tend to induce more abutment removal torque loss and implant conical surface morphological changes than those with metal connections, both initially and after simulated long-term oral use. Zirconia abutments with an alloy base performed similarly to 1-piece titanium abutments.

Advantages of monitoring rT3 and dividing LT3 dose in the treatment of consumptive hypothyroidism associated with infantile hepatic hemangioma.

OBJECTIVES: In consumptive hypothyroidism associated with infantile hepatic hemangiomas (IHH), elevated reverse triiodothyronine (rT3) is known due to elevated D3. This report shows that rT3 is a new indicator of IHH progression and that three divided doses of LT3 per day were more effective than a single dose. CASE PRESENTATION: A 23 day-old boy was diagnosed with diffuse IHH and severe hypothyroidism with high rT3. Propranolol and LT4 were administered. Hemangiomas gradually diminished and rT3 decreased, but the thyroid-stimulating hormone remained elevated, and free triiodothyronine (fT3) did not normalize after 2 weeks of treatment. Liothyronine (LT3) was started as a single dose and then divided into three doses after 1 week, which stabilized thyroid function. CONCLUSIONS: rT3 levels were less variable and decreased in conjunction with tumor shrinkage; thus, rT3 is an indicator of therapeutic outcomes for IHH. LT3 administered in divided doses aided in managing IHH-associated hypothyroidism.

Incomplete sagittal septum of the bladder with cystolithiasis.

Introduction: Incomplete sagittal septum of the urinary bladder is an extremely rare congenital anomaly and one of the variations in bladder duplication. Herein, we report a case of incomplete sagittal septum of the bladder with cystolithiasis. Case presentation: A 20-year-old man was referred to our department for examination and treatment of symptomatic cystolithiasis and a suspected giant ureterocele on the left side. Cystoscopy and urography performed under general anesthesia revealed anatomical structures suggestive of the sagittal septum of the bladder. Subsequently, transurethral septostomy and cystolithotripsy were performed. The detrusor muscle was microscopically identified, leading to the diagnosis of an incomplete sagittal septum of the bladder. Conclusion: Although extremely rare, an incomplete sagittal septum of the bladder may be difficult to differentiate from a ureterocele, and should be considered when a large cystic lesion is found in the bladder.

Anti-inflammatory and immune-mediated therapy for a case of febrile infection-related epilepsy syndrome with rapid recurrence.

Febrile infection-related epilepsy syndrome (FIRES) is a disease of unknown etiology, characterized by refractory frequent focal seizures, which require prolonged intensive care. We successfully treated a boy with FIRES with anti-inflammatory and immunosuppressive therapy. This case suggests that an autoimmune mechanism may play a role in the development of FIRES.

Multidrug-Resistant Corynebacterium striatum Developed During Treatment of Ommaya Reservoir Infection.

Corynebacterium striatum, a common component of the skin and mucosal microbiota of both immunocompetent and immunocompromised individuals, has become an emerging pathogen, colonizing indwelling medical devices and causing infections at multiple sites. A 3-year-old boy with an Ommaya reservoir in the right ventricle and a medical history of grade 3 intraventricular hemorrhage, Hirschsprung disease, catheter-related methicillin-resistant Staphylococcus aureus bacteremia, and congenital central hypoventilation syndrome was hospitalized for Ommaya reservoir infection with C. striatum. He was treated with ampicillin, to which the initial isolate was susceptible. C. striatum may have acquired multiple-drug resistance during the antibiotic treatment due to biofilm production. The Ommaya reservoir was replaced by external ventricular drainage. Cultures of the removed Ommaya reservoir, and cerebrospinal fluid samples grew C. striatum, which was susceptible to meropenem and vancomycin and resistant to other antibiotics. The antibiotic was switched to vancomycin to treat this new multidrug-resistant strain. After 8 days of vancomycin treatment, the cerebrospinal fluid culture obtained by a lumbar puncture was negative for C. striatum. In cases of device-associated infections caused by biofilm-producing bacteria, it is desirable to remove the device as soon as possible.

Fracture Resistance of Zirconia Abutments with or without a Titanium Base: An In Vitro Study for Tapered Conical Connection Implants.

Dental implants with tapered conical connections are often combined with zirconia abutments for esthetics; however, the effect of the titanium base on the implant components remains unclear. This study evaluated the effects of a titanium base on the fracture resistance of zirconia abutments and damage to the tapered conical connection implants. Zirconia (Z) and titanium base zirconia (ZT) abutments were fastened to Nobel Biocare (NB) implants and Straumann (ST) implants and subjected to static load testing according to ISO 14801:2016. The experiments were performed with 3 mm of the platform exposed (P3) and no platform exposed (P0). The fracture loads were statistically greater in the titanium base abutments than the zirconia abutments for the NB and ST specimens in the P0 condition. In the P3 condition of the ST specimens, the deformation volume of the ZT group was significantly greater than the Z group. The titanium base increased the fracture resistance of the zirconia abutments. Additionally, the titanium base caused more deformation in the P3 condition. The implant joint design may also affect the amount of damage to the implants when under a load. The mechanical properties of the abutment should be considered when selecting a clinical design.

Influence of Liquid on the Tooth Surface on the Accuracy of Intraoral Scanners: An In Vitro Study.

PURPOSE: To assess the influence of liquid attached on the tooth surfaces on the accuracy (trueness and precision) of intraoral scanners and the effectiveness of the drying method (using compression air) to exclude the influence of liquid on the scanning results. MATERIALS AND METHODS: A mandibular jaw model was scanned using an industrial computed tomography scanner to obtain a reference model. A scanning platform was designed to simulate three specific tooth surface states (dry, wet, blow-dry). Two kinds of liquids (ultra-pure water and artificial saliva) were used for the test. Two intraoral scanners (Trios 3 and Primescan) were used to scan the mandibular jaw model 10 times under each condition. All scanning data were processed and analyzed using dedicated software (Geomagic Control 2015). Trueness and precision comparison were conducted within the 12 groups of 3D models divided based on different intraoral scanners and liquids used under each condition. The root mean square (RMS) value was used to indicate the difference between the aligned virtual models. The color maps were used to evaluate and observe the deviation distribution patterns. The 3-way ANOVA (condition, intraoral scanner, liquid) followed by the Tukey test were used to assess precision and trueness. The level of significance was set at 0.05. RESULTS: The mean RMS values obtained from wet condition were significantly higher than those of the dry and blow-dry condition (p < 0.001, F = 64.033 for trueness and F = 54.866 for precision), which indicates less accurate trueness and precision for wet condition. For two different types of liquids, the mean RMS value was not significantly different on trueness and precision. The deviations caused by liquid were positive and mainly distributed in the pits and fissures of the occlusal surface of posterior teeth, the interproximal area of the teeth, and the margin of the abutments. CONCLUSIONS: Liquid on the tooth surface could affect intraoral scanning accuracy. Blow-drying with a three-way syringe can reduce scanning errors.

Development of Acute Inflammatory Demyelinating Polyneuropathy 11 Days after Spinal Surgery: A Case Report and Literature Review.

Guillain-Barré syndrome (GBS) usually has a good prognosis; however, patients may develop sequelae without prompt treatment. We herein describe an 81-year-old woman who developed acute-onset excruciating thigh pain and weakness in her lower extremities after spinal surgery. We diagnosed acute inflammatory demyelinating polyradiculoneuropathy by a nerve conduction study, which showed findings of demyelination without cerebrospinal fluid analysis because of a spinal prosthesis. Although anti-GM1 and anti-GalNAc-GD1a antibodies were positive, the patient was clinically diagnosed with acute inflammatory demyelinating polyradiculoneuropathy (a subtype of GBS), not acute motor axonal neuropathy. She recovered well with immunoglobulin therapy. A literature review of 18 cases revealed that unexplained weakness, areflexia, and numbness of the extremities after spinal surgery, a shorter time from spinal surgery to symptom onset to general GBS, abnormal nerve conduction study results, normal spinal imaging findings, and the development of atypical symptoms such as cranial and autonomic nerve syndrome and respiratory failure are useful for diagnosing GBS when cerebrospinal fluid examination cannot be performed after spinal surgery.

Effects of Implant-Abutment Connection Type and Inter-Implant Distance on Inter-Implant Bone Stress and Microgap: Three-Dimensional Finite Element Analysis.

The attainment of a good aesthetic outcome in dental implant treatment requires inter-implant papilla reconstruction, which is very difficult to perform. Maintenance of the inter-implant bone is essential for maintenance of the inter-implant papilla. The aim of this study was to investigate the mechanical influences of the implant-abutment connection type and inter-implant distance on the inter-implant bone by using three-dimensional finite element analysis. Three computer-aided design models of two-piece implants were designed: external connection (EC), internal connection (IC), and conical connection (CC). In each model, two identical implants were placed with inter-implant distances of 3.0, 2.5, and 2.0 mm. The maximum principal stress and microgap were evaluated. The stress values of the inter-implant bone decreased in the following order: IC, EC, and CC. The microgap decreased in the following order: EC, IC, and CC. Regardless of the type of implant-abutment connection, the stress of the inter-implant bone increased as the inter-implant distance decreased. The microgap barely changed as the inter-implant distance decreased. A CC implant is a mechanically advantageous implant-abutment connection type for maintenance of the inter-implant bone. With an inter-implant distance of less than 3.0 mm, use of a CC implant might suppress absorption of the inter-implant bone.

Novel Urinary Glycan Biomarkers Predict Cardiovascular Events in Patients With Type 2 Diabetes: A Multicenter Prospective Study With 5-Year Follow Up (U-CARE Study 2).

Background: Although various biomarkers predict cardiovascular event (CVE) in patients with diabetes, the relationship of urinary glycan profile with CVE in patients with diabetes remains unclear. Methods: Among 680 patients with type 2 diabetes, we examined the baseline urinary glycan signals binding to 45 lectins with different specificities. Primary outcome was defined as CVE including cardiovascular disease, stroke, and peripheral arterial disease. Results: During approximately a 5-year follow-up period, 62 patients reached the endpoint. Cox proportional hazards analysis revealed that urinary glycan signals binding to two lectins were significantly associated with the outcome after adjustment for known indicators of CVE and for false discovery rate, as well as increased model fitness. Hazard ratios for these lectins (+1 SD for the glycan index) were UDA (recognizing glycan: mixture of Man5 to Man9): 1.78 (95% CI: 1.24-2.55, P = 0.002) and Calsepa [High-Man (Man2-6)]: 1.56 (1.19-2.04, P = 0.001). Common glycan binding to these lectins was high-mannose type of N-glycans. Moreover, adding glycan index for UDA to a model including known confounders improved the outcome prediction [Difference of Harrel's C-index: 0.028 (95% CI: 0.001-0.055, P = 0.044), net reclassification improvement at 5-year risk increased by 0.368 (0.045-0.692, P = 0.026), and the Akaike information criterion and Bayesian information criterion decreased from 725.7 to 716.5, and 761.8 to 757.2, respectively]. Conclusion: The urinary excretion of high-mannose glycan may be a valuable biomarker for improving prediction of CVE in patients with type 2 diabetes, and provides the rationale to explore the mechanism underlying abnormal N-glycosylation occurring in patients with diabetes at higher risk of CVE. Trial Registration: This study was registered with the University Hospital Medical Information Network on June 26, 2012 (Clinical trial number: UMIN000011525, URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000013482).